Association of Elevated Plasma Interleukin-18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome.

Pubmed ID: 31206358

Pubmed Central ID: PMC6629502

Journal: Critical care medicine

Publication Date: Aug. 1, 2019

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA.

MeSH Terms: Humans, Male, Adult, Female, Middle Aged, Retrospective Studies, Intensive Care Units, Acute Lung Injury, Pulmonary Alveoli, Sepsis, Interleukin-18, Respiratory Distress Syndrome

Grants: R37 HL051856, R01 HL051856, R01 HL055330, KL2 TR002385, P01 HL114501, UL1 TR003142, R01 HL112747, K23 HL125663, R01 HL111024

Authors: Matthay MA, Liu KD, Wheeler A, Steingrub J, Desai M, DeSouza L, Mogan S, Rogers AJ, Guan J, Trtchounian A, Hunninghake GM, Kaimal R, Kozikowski LA, Yoon JH, Nakahira K, Choi AM, Baron RM

Cite As: Rogers AJ, Guan J, Trtchounian A, Hunninghake GM, Kaimal R, Desai M, Kozikowski LA, DeSouza L, Mogan S, Liu KD, Matthay MA, Steingrub J, Wheeler A, Yoon JH, Nakahira K, Choi AM, Baron RM. Association of Elevated Plasma Interleukin-18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome. Crit Care Med 2019 Aug;47(8):1089-1096.

Studies:

Abstract

OBJECTIVE: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial. DESIGN: Retrospective analysis of randomized controlled clinical trial. SETTING: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis. PATIENTS: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population. INTERVENTIONS: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge. MEASUREMENTS AND MAIN RESULTS: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however. CONCLUSIONS: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.